The incidence of both Type 2 and gestational diabetes increase with age, due in part to a decline in b cell proliferation as individuals age. This may be due in part to the increased expression of cell cycle inhibitors in aged b cells, and a concomitant decrease in expression of cell cycle activators. However, insulin resistant states, such as obesity and pregnancy, normally stimulate replication in adult quiescent b cells. Failure to increase b cell mass in the face of insulin resistance can lead to Type 2 diabetes or gestational diabetes. The FoxM1 transcription factor is expressed in proliferating cells, regulates cell cycle genes, and promotes cell cycle progression. The Gannon lab discovered that mice lacking FoxM1 in their pancreas became diabetic due to a failure of b cell mass expansion after four weeks of age. We subsequently showed that FoxM1 is essential for b cell replication in response to all stimuli tested including pancreatic injury, pregnancy, and high fat diet. b cell proliferative stimuli were all found to induce Foxm1 gene expression in vivo. We hypothesize that FoxM1 represents a nodal point at which all stimulatory pathways for b cell proliferation intersect, and that FoxM1 gene expression and protein activity are enhanced by b cell proliferative stimuli. We predict that FoxM1 represent an excellent candidate for enhancement of replication in older b cells and thus may be a target for improving b cell mass expansion in diabetic individuals. These hypotheses will be tested using in vitro and in vivo approaches. In vitro, we will determine whether pharmacological activators of known b cell proliferative second messenger signaling pathways induce Foxm1 gene expression and/or protein activity in islets isolated from mice of different ages. In vivo, we will use microarray analyses to determine the effects of loss of FoxM1 on the b cell transcriptome under normal and stimulatory conditions. We will also examine whether FoxM1 mainly acts to promote b cell replication through its repression of cell cycle inhibitors. Finally, we will test whether expression of an activated form of FoxM1 in aged b cells is able to overcome the decline in replication that normally occurs with age. A thorough understanding of how FoxM1 functions to regulate b cell replication will lead to strategies for enhancing b cell proliferation and augmenting b cell mass for the treatment of diabetes, a disease that currently affects 16% of the veteran population and is expected in to increase even further in the coming years.